Substituted indoles play a pivotal role in drug discovery, culminating in launch of several drugs including many molecules in clinical pipeline. The discovery and development of drugs to treat allergic conditions and asthma have attracted great importance in pharmaceutical industry. The success rate in this area of research has been significant because, the human intralobar airways have a single receptor for peptido leukotrienes. There has been a great progress reported in identifying selective peptide leukotriene antagonists. Indole and indazole compounds have been extensively investigated as selective antagonists of the leukotriene pathway. All these efforts have culminated in launching Zafirlukast as the oral leukotriene receptor antagonist (LTRA) for the maintenance treatment of asthma, prescribed in combination with bronchodilators and steroids. Some other marketed products with indole skeleton are panabinostat, oxindole, tropisetron etc.
Traditionally, these classes of compounds are synthesized from prefabricated indole which offers lesser flexibility in substitutions in the benzene ring of indole. Thus, a non-conventional strategy with formation of indole as the key step was the target of this preparation process. Therefore, the process for preparation of Zafirlukast starts with the construction of 3-aroylindoles, followed by further process steps to obtain the Zafirlukast and corresponding analogs library. There are several methods reported in the literature for the formation of indole moiety, which are generally carried out using transition metal catalysts. Some of these references are: (a) Eur. J. Org. Chem. 2012, 2549; (b) Angew. Chem. Int. Ed. 2012, 51, 3766; (c) J. Am. Chem. Soc. 2011, 133, 11924; (d) Angew. Chem. Int. Ed. 2009, 48, 8078; (e) Org. Lett. 2013, 15. 1802; (f) Chem. Commun. 2014, 50, 10445; (g) Chem. Commun. 2013, 49, 1410. However, there are no process methods which are based on peroxide free and transition metal-free cyclization protocol for indole formation. Till date, several procedures on the synthesis and applications for the Zafirlukast and related compounds/intermediates are reported in literature with varying levels of success and some of them are (a) U.S. Pat. No. 4,859,692; (b) U.S. Pat. No. 5,319,097; (c) U.S. Pat. No. 5,993,859; (d) WO2002046153; (e) EP0199543; (f) GB8509882; (g) GB8525658; (h) IN2899/CHE/2007; (i) US20090149662; (j) J. Med. Chem, 33, 1990, 1781; (k) CN105367478; (l) CN103396353; (m) CN102199117; (n) CN101104601; (o) OPRD 2009, 13, 67; (p) Biomed. Chromatogr., 22, 2008; 645; (q) Cryst., Growth Des. 2015, 15, 4162. Though, several of these methods are practical at laboratory level, only few of them are useful at industrial production. Most of these reported methods are difficult to be practiced at the industrial production due to one or more of the following factors: (a) expensive reagents and/or raw materials (b) uneven temperature and/or reaction times (c) multi-step process (d) operationally difficult reaction conditions/parameters.